Limits...
Structural and Physical Basis for Anti-IgE Therapy.

Wright JD, Chu HM, Huang CH, Ma C, Chang TW, Lim C - Sci Rep (2015)

Bottom Line: Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors?These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI.They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] The Genomics Research Center, Academia Sinica 115, Taiwan.

ABSTRACT
Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Å omalizumab-Fab structure, a docked IgE-Fc/omalizumab-Fab structure consistent with available experimental data, and the free energy contributions of IgE residues to binding omalizumab, CD23, and FcεRI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

No MeSH data available.


Related in: MedlinePlus

The IgE/omalizumab interface.(a) Two omalizumab-Fab molecules (green) binding to two IgE Cε3-4 domains (marine/blue) with the Cε2 domains (cyan) in the extended conformation. (b) Omalizumab-binding site (yellow/wheat) on the IgE Cε3 domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4481376&req=5

f4: The IgE/omalizumab interface.(a) Two omalizumab-Fab molecules (green) binding to two IgE Cε3-4 domains (marine/blue) with the Cε2 domains (cyan) in the extended conformation. (b) Omalizumab-binding site (yellow/wheat) on the IgE Cε3 domain.

Mentions: The orientation of omalizumab-Fab bound to IgE allows for two omalizumabs to bind to a single IgE (Fig. 4a), in agreement with experimental results33.


Structural and Physical Basis for Anti-IgE Therapy.

Wright JD, Chu HM, Huang CH, Ma C, Chang TW, Lim C - Sci Rep (2015)

The IgE/omalizumab interface.(a) Two omalizumab-Fab molecules (green) binding to two IgE Cε3-4 domains (marine/blue) with the Cε2 domains (cyan) in the extended conformation. (b) Omalizumab-binding site (yellow/wheat) on the IgE Cε3 domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481376&req=5

f4: The IgE/omalizumab interface.(a) Two omalizumab-Fab molecules (green) binding to two IgE Cε3-4 domains (marine/blue) with the Cε2 domains (cyan) in the extended conformation. (b) Omalizumab-binding site (yellow/wheat) on the IgE Cε3 domain.
Mentions: The orientation of omalizumab-Fab bound to IgE allows for two omalizumabs to bind to a single IgE (Fig. 4a), in agreement with experimental results33.

Bottom Line: Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors?These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI.They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] The Genomics Research Center, Academia Sinica 115, Taiwan.

ABSTRACT
Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Å omalizumab-Fab structure, a docked IgE-Fc/omalizumab-Fab structure consistent with available experimental data, and the free energy contributions of IgE residues to binding omalizumab, CD23, and FcεRI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

No MeSH data available.


Related in: MedlinePlus